The present invention relates to molecular clusters. In particular, the invention relates to compositions, methods of making and methods of using molecular clusters of solvent mixtures in supercritical fluid.
Supercritical fluids are unique states of matter existing above certain temperatures and pressures. As such, these fluids exhibit a high level of functionality and controllability that can influence not only the macrophysical properties of the fluid, but also influence nano-structures of molecules dissolved in them.
Solvent mixtures in supercritical fluids and pressurized liquids are known to form molecular clusters about dilute solute molecules. These molecular clusters can be described as transient molecular cages and can behave as microscopic reactors. Molecular clusters can confine the space through which trapped molecules can diffuse which can increase the odds that trapped molecules might encounter a reactive collision. Organic solvents have the ability to cluster about dilute solute molecules in mixtures of supercritical fluids and pressurized fluids, and confine the space through which these xe2x80x9ccagedxe2x80x9d molecules can diffuse. Under these circumstances, it can be possible to maintain high reaction efficiency with minute, and possibly stoichiometric amounts of reactants.
The degree to which certain organic solvents cluster in supercritical and pressurized fluids has been studied. For example, acetonitrile has been investigated for its potential to cluster in CO2 above and below the critical point for the mixture. The use of solvents in supercritical fluids to affect the reaction kinetics and the yield of products produced from dilute solute reactant molecules has also been studied. For example, the use of acetonitrile in supercritical carbon dioxide has been investigated for its use as a solvent, as it applies to producing useful quantities of radioactive biomolecules for use in Positron Emission Tomography (PET) in connection with the alkylation reaction between methyiodide and L-xcex1-methyl-N-2-propynyl phenylethylamine (nordeprenyl) to yield L-deprenyl.
In WO 92/20812, certain enzymes were used to selectively catalyze the reaction of only one enantiomer of a chiral compound in supercritical carbon dioxide. Specifically, a racemic mixture of a chiral compound was brought into contact with the enzyme that was only capable of reacting with one enantiomer of the mixture. The chiral product that was obtained was enantiomerically pure and easily separated from the reaction mixture by conventional methods such as extraction, crystallization or evaporation.
U.S. Pat. No. 5,403,703 discloses an enzymatic esterification reaction involving a primary terpene secondary alcohol with a higher fatty acid in a reaction medium of supercritical carbon dioxide in the presence of a lipase. Racemic resolution of the primary terpene secondary alcohol having chirality was achieved by first producing a fatty acid ester of the alcohol having an optical purity of almost 100% and then hydrolyzing the fatty acid ester to convert it back to an alcohol having high optical purity. Furthermore, the reaction velocity of the esterification reaction was found to have increased more than six times when the reaction medium was in supercritical carbon dioxide.
None of the technologies mentioned above disclose the use of fluids as a reaction medium under conditions that cause the reactants to form optically active chiral centers which would not form under ordinary reaction conditions. The technologies mentioned above also do not mention controlling chemical reactions by directing the position of bonding between ligands and molecules. Furthermore, the use of critical clusters for drug synthesis formed by directing the position of bonding between ligands and molecules wherein new chiral centers are formed have not been addressed. Finally, the use of critical clusters for racemic resolution reactions without the use of enzymes has not been addressed.
Thus, there is a need for new compositions which can be used to create optically active chiral centers with the advantages of using supercritical fluids. In addition, there is a need to be able to direct the position where ligands bond to molecules in a chemical reaction. Finally, there is a need to be able to make pharmaceutical compounds and perform racemic resolution reactions using critical clusters.
According to the present invention, it has now been found that molecular clusters formed by the aggregation of substantially optically-pure chiral solvent molecules dissolved in a supercritical fluid and maintained at or close to its critical density can exert certain spatial constraints on encaged solute molecules that allow for the creation of optically active chiral centers as a result of their undergoing a chemical reaction. In addition, certain kinetic control can be exerted over these molecular clusters and encaged reactant solute molecules that allow for control over the position where ligands bond on molecules. It has been found that these qualities can be tuned by adjusting the pressure and/or temperature of the supercritical fluid medium. Finally, pharmaceutical drug synthesis and racemic resolution reactions without the use of enzymes can be accomplished using critical clusters.
One aspect of the invention is directed to a critical cluster for asymmetric synthesis in which the critical cluster contains substantially optically-pure chiral solvent molecules in a supercritical fluid. The solvent molecules are capable of multipoint hydrogen bonding and encaging at least one solute molecule capable of reacting within the cluster to form an optically active chiral center.
Another aspect of the invention is directed to a method of making critical clusters for asymmetric synthesis which includes encaging at least one solute molecule, which is capable of reacting within the critical cluster to form an optically active chiral center, with substantially optically-pure chiral solvent molecules in a supercritical fluid under conditions of temperature and pressure sufficient to form critical clusters. The substantially optically-pure chiral solvent molecules are capable of multipoint hydrogen bonding with the encaged solute molecules.
In yet another aspect, the invention is directed to a method for asymmetric synthesis using critical clusters. This method involves encaging at least one solute molecule with substantially optically-pure chiral solvent molecules in a supercritical fluid under conditions of temperature and pressure sufficient to form critical clusters. The solvent molecules are capable of multipoint hydrogen bonding with the solute molecules. The encaged solute molecules are then reacted within the cluster whereby an optically active chiral center is formed in a product of the reaction.
In a preferred embodiment, the substantially optically-pure chiral solvent molecules of the present invention are secondary alcohol molecules, preferably having from four to about nine carbon atoms. More preferably, the secondary alcohol molecules are selected from the group consisting of S(+)-2-butanol and R(xe2x88x92)-2-butanol. In another embodiment, the solute molecule is benzaldehyde.
In a preferred embodiment, the supercritical fluid that is employed in the present invention is carbon dioxide. The supercritical carbon dioxide is preferably maintained at a pressure from about 71 bar to about 275 bar, more preferably from about 100 bar to about 150 bar, and at a temperature from about 31xc2x0 C. to about 125xc2x0 C., more preferably from about 50xc2x0 C. to about 70xc2x0 C.
In another embodiment, the conditions of temperature and pressure of the supercritical fluid are sufficient to change the electric charge distribution of the solute molecule(s). The weight percentage of cosolvent and solute in the supercritical fluid is preferably from about 1% to about 20%, more preferably from about 5% to about 15%.
In a further embodiment, the solute molecule employed is benzaldehyde and the product formed which has an optically active chiral center is S(+)benzoin.
The invention is also directed to a method of directing the position of bonding between a solute molecule and a ligand. This method involves encaging the solute molecule and the ligand with polar solvent molecules in a supercritical fluid under conditions of temperature and pressure sufficient to change electric charge distribution in the solute molecule.
In one embodiment, the polar solvent molecules are capable of multipoint hydrogen bonding to the solute molecules. These polar solvent molecules can be chiral and can also be substantially optically-pure. In addition, the polar solvent molecules can be secondary alcohol molecules, preferably having from four to about nine carbon atoms. The secondary alcohol molecules can be selected from the group consisting of S(+)-2-butanol and R(xe2x88x92)-2-butanol.
In a preferred embodiment, the supercritical fluid that is employed with the method of directing the position of bonding between a solute molecule and a ligand is carbon dioxide. The supercritical fluid is preferably maintained at a pressure from about 71 bar to about 275 bar, more preferably from about 100 bar to about 150 bar, and at a temperature from about 31xc2x0 C. to about 125xc2x0 C., more preferably from about 50xc2x0 C. to about 70xc2x0 C.
The weight percentage of cosolvent and solute in the supercritical fluid is preferably from about 1% to about 20%, more preferably from about 5% to about 15%.
The ligand employed in the method stated above can be a methyl group and the solute molecule to which the methyl group bonds can be ritalinic acid. In such an embodiment, the conditions of temperature and pressure are sufficient for directing the bonding of the methyl group to the oxygen site of the carboxylic acid functional group on ritalinic acid forming the drug ritalin. The methyl group can come from an methylhalide selected from the group consisting of methyliodide and methylbromide. The polar solvent molecule can also be chiral and capable of multipoint hydrogen bonding to ritalinic acid resulting in an substantially optically-pure ritalin product. The polar solvent molecule can be acetonitrile.
In another aspect, the invention is directed to a method of making pharmaceutical compounds using critical clusters. This method involves encaging a solute molecule, which is capable of forming a chiral center, and a ligand with polar solvent molecules in a supercritical fluid under conditions of temperature and pressure sufficient to change electric charge distribution of the solute molecule. The encaged solute molecule and ligand are then reacted whereby the ligand bonds to the solute molecule forming a chiral center.
The polar solvent molecules can be chiral and they can also be substantially optically-pure. In addition, the polar solvent molecules can be capable of multipoint hydrogen bonding to the solute molecule. When the polar molecules are chiral, the chiral center which is formed can be substantially optically-pure. The polar solvent molecules can be secondary alcohol molecules, preferably having from four to about nine carbon atoms. In addition, the secondary alcohol molecules can be selected from the group consisting of S(+)-2-butanol and R(xe2x88x92)-2-butanol.
In a preferred embodiment, the supercritical fluid employed for making pharmaceutical compounds is carbon dioxide. The supercritical carbon dioxide is preferably maintained at a pressure from about 71 bar to about 275 bar, more preferably from about 100 bar to about 150 bar, and at a temperature from about 31xc2x0 C. to about 125xc2x0 C., more preferably from about 50xc2x0 C. to about 70xc2x0 C.
The weight percentage of cosolvent and solute in the supercritical fluid employed for making pharmaceutical compounds is preferably from about 1% to about 20%, more preferably from about 5% to about 15%.
In one embodiment, the solute molecule is phenylethylamine and the ligand is a methyl group. The methyl group can come from a methylhalide selected from the group consisting of methyliodide and methylbromide. In this embodiment, the conditions of temperature and pressure can be made sufficient to direct the bonding of the methyl group to the alpha position of phenylethylamine to form amphetamine as the product.
In yet another aspect, the invention is directed to a method for racemic resolution using critical clusters. This method involves encaging racemic mixtures of solute molecules with substantially optically-pure chiral solvent molecules in a supercritical fluid under conditions of temperature and pressure sufficient to form critical clusters. The solvent molecules are capable of multipoint hydrogen bonding with the solute molecules. The encaged solute molecules are nonenzymatically reacted to enhance the optical purity of the solute molecules.
In a preferred embodiment, the substantially optically-pure chiral solvent molecules employed in the method for racemic resolution are secondary alcohol molecules, preferably having from four to about nine carbon atoms. More preferably, the secondary alcohol molecules are selected from the group consisting of S(+)-2-butanol and R(xe2x88x92)-2-butanol.
In a preferred embodiment, the supercritical fluid that is employed with the method for racemic resolution using critical clusters is carbon dioxide. The supercritical carbon dioxide is preferably maintained at a pressure from about 71 bar to about 275 bar, more preferably from about 100 bar to about 150 bar, and at a temperature from about 31xc2x0 C. to about 125xc2x0 C., more preferably from about 50xc2x0 C. to about 70xc2x0 C.
In another embodiment, the conditions of temperature and pressure of the supercritical fluid can be made sufficient to change the electric charge distribution of the solute molecule. The weight percentage of cosolvent and solute in the supercritical fluid is preferably from about 1% to about 20%, more preferably from about 5% to about 15%.
As a result of the present invention, critical clusters can be made in supercritical fluids and used in microscale reactions to influence chemical reactions and form optically active chiral centers.
The present invention is therefore advantageous in that it allows the formation of optically active chiral centers that would not form under ordinary reaction conditions. Other advantages of the present invention include the capacity to direct the position of bonding between ligands and molecules in supercritical fluids by adjusting the pressure and temperature of the supercritical fluid. Still other advantages of the present invention include the potential for new synthetic pathways for producing pharmaceutical compounds such as amphetamine by directing the bonding of a methyl group to the alpha position of phenylethylamine by controlling the temperature and pressure of the reaction. Finally, the present invention provides the advantage of performing racemic resolution reactions in critical clusters without the need to use enzymes.
Additional objects, advantages and novel features of the invention will be set forth in part in the description and examples which follow, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.